The goal of this proposal is to continue the development of new methods of linkage and association analysis, and to combine the new methods with existing linkage and association methods for nuclear families into a single software package. Over the course of the past three years we have developed and released 5 software programs for the genetic analysis of complex traits including software for affected sib-pair linkage mapping, software for association analysis in general pedigrees, software for ordered subset linkage mapping and a general simulation package to explore the properties of these and other software packages. We propose to continue the development of these methods and accompanying software in the following ways: 1) Continue development of empirical p-value methods and accompanying software. The simulation package we developed and distributed is available for simulation of general pedigrees, which can include an observed marker map and observed allele frequencies. Our goal is to expand this package to simulate from the observed pedigree structures, including indicators of the observed phenotypes and genotypes. 2) Develop and distribute software for family-based association in the presence of linkage. In the course of our simulation studies comparing available software packages for family-based association, we observed grossly inflated type I errors in regions of linkage for one of the tests. We propose a new test that adjusts for the presence of linkage in families and gives the proper type 1 error rates. 3) Continue development of the ordered subset analysis (OSA) methods and software to incorporate more than one trait through recursive partitioning methods that use OSA to partition the linkage evidence and to apply this method to family-based association analysis. 4) Develop methods that will incorporate a variety of statistical tests, expression and proteomics results as well as incorporate genetic features emerging from the Human Genome Project such as identified genes, Haplotype Blocks, hot spots of recombination and at-risk sequences. Our research into methods development, assessment and comparison has been aided by the application of these new methods to a variety of ongoing applied linkage and association projects. Our collaborators have tested new software and have discussed the practical consequences of choices made during methods development and software programming. We will continue to utilize this resource to develop realistic and practical guidelines for application of these methods.